MELANOMA CELL SURFACE PROTEOGLYCANS IN METASTASIS

描述：(改编自研究人员摘要)黑色素瘤软骨素 硫酸盐蛋白多糖(MCSP)，又称高分子量黑色素瘤 相关抗原(HMW-MAA)是一种大的、高度抗原性的细胞表面 在黑色素瘤中显著上调的蛋白多糖。MCSP正在被 作为黑色素瘤疫苗开发的积极目标，由于其 限制性表达和抗原性。尽管它有潜在的临床价值 重要性，对MCSP在黑色素瘤中的作用知之甚少 进步。以前的研究表明，MCSP与粘附性、运动性或 细胞生长控制。他提供了数据来证明抑制 反义寡核苷酸表达MCSP抑制肿瘤侵袭 在软琼脂中体外生长。他已经证明了MCSP作为一种 黏附分子，部分是通过增强a4b1整合素的活性，a4b1整合素 肿瘤侵袭和抑制的中介物。此外，他还确定了一部小说 MCSP刺激的信号通路。MCSP的激活导致了 接头蛋白p130Cas的结合和酪氨酸磷酸化 与肿瘤的运动性和侵袭性有关。该信号通路还包括 MCSP与CDC42家族GTP的相互作用 丝状孔的形成、细胞的运动和生长。此外，Ack-1，一种酪氨酸 与活性的(即，GTP结合的)Cdc42结合的激酶，是 MCSP诱导p130Cas酪氨酸磷酸化。总而言之，数据是 与MCSP通过以下途径促进肿瘤生长和侵袭的模型一致 隔离信号复合体的细胞内成分以响应 外部刺激。在本申请中，他将进一步定义信令 并研究其对黑色素瘤生长、侵袭和转移的重要性。 此外，尽管MCSP序列已经发布，但它以前从未发布过 都被克隆了。他最近扩增了MCSP的全长编码序列 通过RT-PCR人黑色素瘤基因的表达，并正在将其在 不含MCSP的黑色素瘤细胞。这一克隆将使他们能够 审查MCSP、ITS之间的结构和功能关系 细胞外刺激及其细胞内信号转导。他提议 三个具体目标：1.评估MCSP表达和 在恶性黑色素瘤细胞的生长、侵袭和转移中的作用。2. Ack-1在MCSP诱导的心肌细胞酪氨酸磷酸化中的作用机制 P130Cas，并探讨其在肿瘤存活、生长和转移中的作用机制。 恶性黑色素瘤细胞。3.定义MCSP核心的功能域 信号转导和黑色素瘤生长、侵袭和转移所需的蛋白质。

DESCRIPTION: (Adapted from the investigator's abstract) Melanoma chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight melanoma associated antigen (HMW-MAA) is large, highly antigenic cell surface proteoglycan that is dramatically upregulated in melanoma. MCSP is being actively pursued as a target for melanoma vaccine development due to its restricted expression and antigenic properties. Despite its potential clinical importance, relatively little is known about the role of MCSP in melanoma progression. Previous studies have implicated MCSP in adhesion, motility, or cellular growth control. He presents data to demonstrate that inhibition of MCSP expression by anti-sense oligonucleotides inhibits tumor invasion and growth in soft agar in vitro. He has demonstrated that MCSP functions as an adhesion molecule, in part by enhancing the activity of a4b1 integrin, a mediator of tumor invasion and arrest. In addition, he has identified a novel signaling pathway stimulated by MCSP. Activation of MCSP leads to the rapid association and tyrosine phosphorylation of p130cas, an adapter protein implicated in tumor motility and invasion. This signaling pathway also involves the association of MCSP with cdc42, a rho-family GTPase that mediates filopodial formation, cell motility and growth. Furthermore, Ack-1, a tyrosine kinase that associates with active (i.e., GTP bound) cdc42, is required for MCSP induced tyrosine phosphorylation of p130cas. Collectively the data are consistent with a model in which MCSP enhances tumor growth and invasion by sequestering intracellular components of a signaling complex in response to an external stimulus. In this application he will further define that signaling complex and study its importance for melanoma growth, invasion and metastasis. Additionally, although the MCSP sequence is published, it has not previously been cloned. He has recently amplified the full-length coding sequence for MCSP by RT-PCR of human melanoma mRNA and are in the process of expressing it in transfected melanoma cells which lack MCSP. This clone will enable them to examine the structural and functional relationships between MCSP, its extracellular stimuli, and its intracellular signal transduction. He proposes three specific aims: 1. To evaluate the importance of MCSP expression and function in the growth, invasion and metastasis of malignant melanoma cells. 2. To delineate the mechanism of Ack-1 in MCSP induced tyrosine phosphorylation of p130cas and to study this mechanism in the survival, growth and metastasis of malignant melanoma cells. 3. To define functional domains of the MCSP core protein required for signaling and melanoma growth, invasion and metastasis.